The molecular genetics analysis of neoplastic conditions of the female genital tract including endometrial carcinoma, uterine sarcoma, uterine leiomyoma and ovarian carcinoma are under study. Significant progress has been achieved in defining the molecular genetic basis of these tumors including defects in pathways that normally function to maintain the stability of the genome. Analysis of these cancers, particularly endometrial cancer has defined a subset that has the molecular genetic phenotype of microsatellite instability. Microsatellite instability is the result of defective DNA mismatch repair, which normally functions to correct DNA replication errors. Inactivation of this pathway may involve mutation or epigenetic silencing of several genes. Current study involves the mechanism for the epigenetic inactivation as well as the contribution of this pathway to carcinogenesis. We are currently defining the genetic targets of instability that may be implicated in human tumor development. In addition, we are studying the role of mismatch repair proteins in the cellular response to oxidant stress and repair of mitochondrial damage. This will be the final year for this project. A subset of these projects will be conducted in project ES- 23003 beginning FY00. - endometrium, mismatch repair, single stranded conformation polymorphism detection (SSCP), cancer, PTEN